What Is Shigella Infection

  • Amani Doklaija Master of Science, pharmaceutical science route, clinical biochemistry, and toxicology specialism – UEL (University of East London), London, UK

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Introduction

Shigella is a type of gram-negative rod-shaped bacteria that belongs to the Enterobacteriaceae family and includes 4 species: shigella dysenteriae, shigella boydii, shigella flexneri, and Shigella sonnei. Shigella causes a form of severe diarrhoea known as Shigellosis or bacillary dysentery, it affects humans, however, the high risk groups are very young people, elderly, and immunocompromised individuals. Shigellosis is more common in developing countries. Shigella is transmitted via poor hygiene, direct contact, or contaminated food intake; once it is ingested, it multiplies in the small intestine and gets access into the colon, where it releases its enterotoxins and serotype toxin 1, which results in bloody or watery diarrhoea.1,2 

Shigella is one of the most common causes of diarrhoea, it accounts for increased rates of morbidity and mortality globally each year, it is one of the significant pathogens responsible for severe bloody or watery diarrhoea which might cause death. Thus, antibiotics play an essential role in reducing prevalence and mortality, though it is still competitive to treat such infections due to an emerging antibiotic resistance to. Drug resistance in Shigella is caused by several mechanisms, such as reduction in cellular membrane permeability, preventing drugs from getting access into the pathogen cells through active efflux pumps and targeting bacterial modification by mutation.3

Etiology

Shigellosis is a food-borne or water-borne disorder caused by a pathogen called Shigella bacteria, which is a gram-negative, anaerobic, non-spore-forming, and rod-shaped bacteria. Shigella has 4 serotypes:

Serotype A: Shigella dysenteriae causes bloody diarrhoea.

Serotype B: Shigella flexneri causes bloody diarrhoea.

Serotype C: Shigella boydii

Serotype D: Shigella soneii, it is characterised by the expression of a specific biochemical marker called ornithine decarboxylase, unlike the other serotypes, they don’t express any unique biochemical marker. Moreover, Shigella soneii causes mild illness of watery diarrhoea. However, Shigella flexneri and Shigella dysenteriae cause bloody diarrhoea, which is of significant severity.2 

Epidemiology 

The number of shigellosis cases is recorded to be one hundred-eighty-eight million per year, while the deaths account for about 1 million annually. 

Approximately 1.5 million cases per year in developed countries.

S. flexneri is the major serotype responsible for causing Shigellosis disease in developing countries. The dominant age group that is infected with Shigellosis is children younger than 4 years old, knowing that there is no specific gender and race predilection for Shigellosis.

Shigellosis incidence is high among daycare centres and residential institutions. Also, Shigellosis cases have been reported in men who have sex with me.2

Pathophysiology

Route of transmission

Humans are the only reservoir for Shigellosis. Regarding developed countries, transmission occurs via faecal-oral route, however, in developing countries it can be via 3 main routes; food-borne, water-borne, and faecal-oral route. Moreover, it is important to mention sexually wise transmission, particularly in men who have sex with men.

Pathogenesis

Through ingestion Shigella enters the small intestine where it multiplies, after that it passes through the large intestine, causes injuries, and complications via producing enterotoxins.

Size of inoculum 

The threshold of organism count to cause the infection is in the range of 10-200 due to two mechanisms: low sensitivity to stomach acid and downregulation of antibacterial proteins of the host by Shigella.

Invasion of epithelial cells

Invasion occurs at the site of the large intestine; Shigella is transported across the epithelium via M cells, which are responsible for the antigen recognition and activation of the immune system; it passes through a specialised form of transport by which it is shuttled through the cytoplasm in membrane-bound vesicles (transcytosis), this results in the release of inflammatory cytokines IL-1 and IL-18, and intestinal inflammation. Following the inflammation process, the macrophages release Shigella. Once apoptosis occurs, Shigella proceeds its invasion mechanism through the epithelium using the intracellular actin polymerisation process, which causes the activation of the nuclear factor in the cells. This nuclear factor produces IL-8, which is responsible for neutrophil stimulation, more inflammation, epithelial damage, and poor absorption of nutrients. Therefore, the process ends with diarrhoea as a result of these inflammatory mechanisms and cellular injury. 

Toxin production

Shigella causes cell injury through another process, which is the release of enterotoxins 1 and 2 that cause diarrhoea. The cytotoxin that is linked to serotype 1 (Shigella dysenteriae) is responsible for the bloody diarrhoea associated with complications such as hemolytic uremic syndrome.2

Clinical manifestations

Common symptoms may include:

  • Mild abdominal discomfort to severe abdominal pain (70%-90%).
  • Mucoid Diarrhoea (70%-80%), then Bloody diarrhoea (30%-50%).

Other symptoms:

  • Fever
  • Nausea and vomiting
  • Anorexia
  • Lethargy
  • Tenesmus

Rare and severe symptoms:

  • Encephalopathy
  • Delirium
  • Seizures
  • Anuria
  • Coma

Vital signs may include fever, tachycardia, tachypnea, and hypotension. An abdominal examination may reveal a distended abdomen with hyperactive bowel sounds.2

Laboratory evaluation

  • Complete blood count (CBC): This includes Leukocytosis, Leukopenia, anaemia, and thrombocytopenia may present.
  • Stool examination: Faecal leukocytes and blood is detected via stool analysis. Stool culture gives better results than a rectal swab culture.
  • Renal function: Very young and elderly groups may show elevated creatinine and BUN.
  • Liver function: In severe stages of the disease, bilirubin might show a mild elevation. 
  • Inflammatory markers: CRP and ESR may be elevated, particularly.
  • Hyponatremia: This occurs due to the syndrome of inappropriate antidiuretic hormone secretion.
  • Stool alpha1-antitrypsin: Found to be high during the acute stage of the disease and in those who failed medical therapy.
  • Blood culture: Blood culture shows more positive outcomes in children than in adults due to disease-associated complications. Bacteremia results in high mortality rates.
  • Polymerase chain reaction (PCR) and ELISA: Rarely to be required, depending on the case. PCR is used to detect pathogenic genes of Shigella, such as virF gene, ipaH gene, and virA gene. However, ELISA is used to detect S. dysenteriae type-1 toxin in stool.2

Treatment and management

It is mandatory to initiate the treatment plan with the medical management in terms of hydration and maintain electrolytes balance, knowing that oral rehydration might be enough in certain cases. 

It is not recommended to use antimotility drugs as loperamide or paregoric due to their negative effect on the recovery time and multiplication of the pathogens, this may prolong the infection.

The antibiotic of choice and selected regimen depend on the age of the patient. Also, the susceptibility test should be done to avoid antibiotic resistance which may vary regionally.

In adults, the antibiotic choice relies on regional resistance. The group of patients with no risk factors of resistance are recommended fluoroquinolone as an antibiotic of choice, while those who are at high risk, international travellers, infected patients in Africa and Asia, immunocompromised patients (HIV patients), and men having sex with men are recommended a third-generation cephalosporin. Additionally, second-generation cephalosporin, trimethoprim-sulfamethoxazole, and ampicillin can be prescribed in Shigellosis as well if there is susceptibility documentation. However, the used antibiotic should be changed if there is a change in susceptibility to resistance. 

In paediatrics, azithromycin is the first-line drug to treat Shigellosis if there is no given data on susceptibility or it is unknown. Azithromycin was found in a randomised trial to be effective in terms of clinical and bacterial patterns in treated infected patients. In South Asia, the most commonly used antibiotics as a first line to treat Shigellosis are ceftibuten and cefixime, this because antibiotic resistance is widely spread in this region. Pivmecillinam is used as an alternative extended-spectrum penicillin to treat Shigellosis infection effectively in reducing diarrhoea duration and eradicating Shigella bacteria in the stool.

In children who have signs of bacteremia as a severe infection of proven or suspected Shigellosis with fever (>39° C), those who have an intolerance to oral medications and immunodeficiency patients, including AIDS, are prescribed parenteral antibiotics instead.

Ceftriaxone is recommended as a single dose or for five days. 

Maintaining adequate hygiene by washing hands after bathroom use and before food preparation is strongly advised. Positive stool cultures become negative after about 2 days of antibiotic initiation. Thus, food handlers should not engage in food preparation if stool cultures are still positive.2

Prognosis

Shigellosis can be a good prognosis if it is treated and diagnosed on time, and patients will recover without further therapeutic plans. However, there are several factors that contribute to poor prognosis, including delay in treatment, prolonged duration of treatment (>7 days), immunocompromised cases, and paediatric and elderly groups with severe complications.2 

Antimicrobial resistance & future research

In Shigella, antimicrobial resistance is multifactorial; it is driven by misuse and overuse of antimicrobials. Resistance rates vary regionally according to the strategy by which the antibiotic is used in Shigellosis. Moreover, poor hygiene, sanitation, and inadequate infection prevention and control plans play an important role in influencing Shigella spread and antimicrobial resistance. Researchers still find it a challenge to control multidrug resistance (MDR) in Shigellosis, especially as it contributes to the development of MDR strains; also, many antimicrobial-resistance mechanisms remain unknown. The most common mechanisms of drug resistance in Shigella are using active efflux pumps to export drugs, decrease in cellular permeability, and enzyme inactivation and gene modification. 

Therefore, more understanding is required for host-microbe relationships to develop alternative therapeutic plans and innovative treatment strategies to prevent and treat Shigellosis. The main challenge is to develop a vaccine that prevents Shigellosis and overcomes multidrug resistance of Shigella strains. There are several conjugate vaccines under development and are ongoing for further assessment, such as a quadrivalent vaccine, which is expected to provide protection against certain serotypes of Shigella. Additionally, the Ipa effector proteins are another promising candidate for a subunit-based vaccine. Further investigations and assessments are needed to overcome the widespread resistance of fluoroquinolones and extended-spectrum cephalosporins.3,5

Summary

  • Shigella is the main pathogen responsible for endemic diarrhoea.
  • Shigella is transmitted through faecal-oral, water-borne, or food-borne routes.
  • The common symptoms of Shigellosis are abdominal discomfort, watery and bloody diarrhoea. Other symptoms include fever, nausea, and vomiting. 
  • Diagnosis of Shigellosis is evaluated through laboratory tests as complete blood count, stool examination, liver functions test, renal function, inflammatory markers, ELISA and polymerase chain reactions and other.
  • In the management and treatment of Shigellosis, hydration and electrolyte maintenance should be initiated, and then the proper antibiotic should be selected, depending on antibiotic susceptibility testing, group age, and other factors.  
  • Antimicrobial resistance is of higher rates; it is the main driver of the evolution of Shigella species. Antimicrobial resistance varies regionally according to demographic, environmental, and hygiene factors, in addition to the strategy used by antimicrobial agents in treating and preventing Shigella species.
  • There is ongoing research to develop several vaccines against multidrug resistance, in addition to new technologies that enhance the understanding of the interaction between infecting organisms and immune cells. Also, further investigations and efforts are needed to overcome widespread resistance to fluoroquinolones and extended-spectrum cephalosporins. 

References

  1. Aslam, Aysha, and Chika N. Okafor. ‘Shigella’. StatPearls, StatPearls Publishing, 2023. PubMed, http://www.ncbi.nlm.nih.gov/books/NBK482337/.
  2. Baker, Stephen, and Hao Chung The. ‘Recent Insights into Shigella: A Major Contributor to the Global Diarrhoeal Disease Burden’. Current Opinion in Infectious Diseases, vol. 31, no. 5, Oct. 2018, pp. 449–54. PubMed Central, https://doi.org/10.1097/QCO.0000000000000475.
  3. Kelly, Meagan, et al. ‘Development of Shigella Conjugate Vaccines Targeting Shigella Flexneri 2a and S. Flexneri 3a Using a Simple Platform-Approach Conjugation by Squaric Acid Chemistry’. Vaccine, vol. 41, no. 34, July 2023, pp. 4967–77. ScienceDirect, https://doi.org/10.1016/j.vaccine.2023.06.052.
  4. Ranjbar, Reza, and Abbas Farahani. ‘Shigella: Antibiotic-Resistance Mechanisms And New Horizons For Treatment’. Infection and Drug Resistance, vol. 12, Oct. 2019, pp. 3137–67. PubMed Central, https://doi.org/10.2147/IDR.S219755.
  5. Zaidi, Mussaret Bano, and Teresa Estrada-García. ‘Shigella: A Highly Virulent and Elusive Pathogen’. Current Tropical Medicine Reports, vol. 1, no. 2, June 2014, pp. 81–87. PubMed Central, https://doi.org/10.1007/s40475-014-0019-6.

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Amani Doklaija

Master of Science, pharmaceutical science route, clinical biochemistry, and toxicology specialism – UEL (University of East London), London, UK

Amani Doklaija holds a Master of Science in Pharmaceutical Science with a specialization in Clinical Biochemistry and Toxicology from the University of East London (UEL), London, UK. She is a registered overseas community and hospital pharmacist with a strong passion for pharmaceutical and biomolecular research and expertise in medical writing.

Amani possesses a solid background in lab-based procedures and is highly motivated and vigilant in completing complex tasks on time. She is skilled in consultative and advisory strategies and has gained a basic foundation in forensic science and toxicology through her master’s studies and online sessions.

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